AB0090 IN VITRO EFFECTS OF METHOTREXATE, ANTI-PDE-4, AND ANTI-JAK TREATMENTS ON HEPATOCYTES STIMULATED BY PSORIATIC ARTHRITIS SERUM
Authors: I. Arias de la Rosa, L. Cuesta López, M. Ruiz-Ponce, M. D. López Montilla, C. López-Medina, C. Perez-Sanchez, M. D. Gahete, N. Herman-Sanchez, C. Lopez-Pedrera, A. Escudero Contreras, E. Collantes Estevez, N. Barbarroja Puerto
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> In recent years, the increased prevalence of liver abnormalities in Psoriatic Arthritis (PsA) has acquired relevance. The liver dysfunction in PsA might be induced by inflammatory components in parallel with the presence of metabolic complications or due to the potential hepatotoxicity of the treatments administered. <h3>Objectives</h3> 1) to analyze the impact of PsA serum on hepatocytes and 2) to investigate the effect of methotrexate, anti-PDE-4, and tofacitinib on hepatocytes treated with PsA serum. <h3>Methods</h3> serum from 12 healthy donors (HDs) and 20 age and sex-matched PsA patients were collected to perform <i>in vitro</i> experiments with the hepatocyte cell line (HEPG2). Cells were treated with HDs serum or PsA serum alone or combined with methotrexate (50µM), roflumilast (1nM), or tofacitinib (250 nM) for 24 hours. The expression of genes related to inflammation, immune response, apoptosis, and liver dysfunction was analyzed by RT-PCR. Cell stress protein array was performed. The levels of 92 inflammatory proteins were determined on the treated hepatocytes using PEA technology (Olink Target 96 Inflammation panel, Cobiomic Biosciences). STRING platform (version 11.5) was used to determine the functional protein association networks. <h3>Results</h3> PsA patients showed a mean disease activity in PsA (DAPSA) of 27.10 ±12.52 (moderate-high disease activity) and significantly elevated levels of c-reactive protein and erythrocyte sedimentation rate with respect to HDs. In hepatocytes, the treatment with PsA serum induced the mRNA expression of ADAM-17, CHUK, CTSD, FAF-1, GDF-15, IFGR-1, IL-6, IL-8, MMP-1, STAT-3, TGF-β and TFPI compared to HDs serum, genes directly associated with biological processes which might impact liver function, such as inflammatory response, immune system, apoptotic process and even directly associated with non-alcoholic fatty liver disease. In addition, PsA serum promoted the expression of 22 proteins mainly involved in cell stress in hepatocytes compared to HDs serum treatment. These proteins are also associated with lipids and atherosclerosis, apoptosis, regulation of inflammatory response, hepatic diseases, and regulation of the extracellular matrix. Surprisingly, 33 out of 92 inflammatory-related proteins were significantly increased in hepatocytes treated with PsA serum compared to HDs serum (36% of proteins). On the other hand, the treatment with anti-PDE-4 promoted the reduction of 11 out of 33 proteins altered by the treatment with PsA serum, proteins mainly involved in leukocyte migration and the immune system. The treatment with anti-JAK reduced levels of 20 out of 33 proteins altered by the treatment with PsA serum. However, the treatment with methotrexate significantly increased the expression of 5 out of 33 proteins altered by the treatment with PsA serum. <h3>Conclusion</h3> 1) PsA serum characterized by the presence of inflammatory components profoundly impacts the hepatocyte function promoting the alteration in proteins and genes involved in the inflammatory response, immune system, and the apoptotic and fibrotic process; 2) the treatment with anti-PDE-4 or anti-JAK is able to partially reverse the deleterious inflammatory effect of PsA serum produced in the hepatocytes. Funded by ISCIII (PI20/00079 and RICOR-RD21/0002/0033), the Andalusian government (1381035-F) co-financed by ERDF. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.